Menopause is a biological process in which a woman's ovaries reduce but do not completely stop their production of female sex hormones. Menopause is diagnosed when menstruation ceases permanently. Changing levels of female sex hormones that precede and postdate menopause often cause a variety of symptoms. Common health issues related to the menopausal transition and menopause include: irregular periods, hot flashes, increased risk of vaginal and/or bladder infection, urge incontinence, stress incontinence, fatigue, depression, loss of muscle mass, increased fat tissue, thinning and loss of skin elasticity, loss of bone tissue, impaired cognition, and an increased prevalence of cardiovascular disease.
One therapy used to combat symptoms associated with changing levels of female sex hormones is hormone replacement therapy (HRT). HRT is the administration of the female hormones including estrogen, progesterone, and androgens. One form of HRT is estrogen replacement therapy (ERT), which is the administration of estrogen alone. It is believed that HRT and ERT help in relieving symptoms of menopause and can be used to combat osteoporosis and to prevent the early onset of heart disease, two conditions often associated with post-menopause.
The use of HRT for bone loss prevention in post-menopausal women is well precedented. The normal protocol calls for estrogen supplementation using such formulations containing estrone, estriol, ethynyl estradiol, 17β-estradiol, esterified estrogens, or conjugated estrogens isolated from natural sources (i.e. PREMARIN conjugated estrogens from Wyeth-Ayerst) or synthetic estrogens. In some patients, ERT therapy may be contraindicated due to the proliferative effects of unopposed estrogens (estrogens not given in combination with progestins) have on uterine tissue. This proliferation is associated with increased risk for endometriosis and/or endometrial cancer. The effects of unopposed estrogens on breast tissue are less clear, but are of great concern to clinicians and patients alike.
Certain non-steroidal anti-estrogens have been shown to maintain bone mass in the ovariectomized rat model as well as in human clinical trials. Tamoxifen (sold as NOVADEX brand tamoxifen citrate by Zeneca Pharmaceuticals, Wilmington, Del.), for example, is a useful palliative for the treatment of breast cancer and has been demonstrated to exert an estrogen agonist-like effect on the bone, in humans. However, it is also a partial agonist in the uterus and this is cause for some concern. Raloxifene, a benzothiophene anti-estrogen, has been shown to stimulate uterine growth in the ovariectomized rat to a lesser extent than Tamoxifen while maintaining the ability to spare bone. A suitable review of tissue selective estrogens is seen in the article “Tissue-Selective Actions Of Estrogen Analogs”, Bone Vol. 17, No. 4, October 1995, 181S-190S.
Further, the long term benefits of HRT and ERT remain questionable due to concerns regarding safety and efficacy. As noted above, HRT and/or ERT may increase an individual's risk of developing cancer. Specifically, it has been reported that prolonged exposure of the breast tissue to estrogen for five or more years of exogenous ERT is linked to an increased risk of breast cancer (Collaborative Group on Hormonal Factors in Breast Cancer, Lancet, 350:1047-1059).
Estrogens are degraded in the intestinal tract and rapidly metabolized by the liver. Specifically, estrogens undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. The estrogen concentration encountered by the liver is generally four-fold to five-fold greater than estrogen levels in peripheral blood (the “first pass effect”). Administration of oral estrogens present high levels to the liver and may lead to an undesirable increase in the production of certain coagulation factors and renin substrates by the liver. Therefore, there is a need for therapeutic agents that are pharmaceutically effective at those regions where they are required.
An oral daily dose of 1 mg 17β-estradiol is considered to be equivalent, in terms of clinical efficacy, to biweekly 50 μg transdermal estradiol. This dose comparison may be misleading, however, because it does not account for large diffusion in estradiol metabolite concentrations nor does it account for the increase in sex hormone-binding globulin (SHBG) after oral, but not transdermal, ERT (Vehkavaara, S. et al., “Differential effects of oral and transdermal estrogen replacement therapy on endothelial function in postmenopausal women,” Circulation, 102:2687-2693 (2000)). The long term consequences of this SHBG-binding variance has not been documented in clinical trials, but does account for many instances of ‘non-response to adequate ERT’ experienced by women in clinical practice.
Because of increased SHBG binding (and possibly other factors), more estrogen is needed after oral ERT to achieve a clinical response equivalent to that obtained by non-oral ERT. Only 5% of oral estradiol is bioavailable following the first-pass hepatic metabolism of oral estradiol. There is only minimal first-pass metabolism of non-oral estradiol (Kuhnz et al., “Pharmacokinetics of estradiol, free and total estrone, in young women following single intravenous and oral administration of 17 beta-estradiol,” Arzneimittelforschung, 43:966-973 (1993)). Thus, high doses of estrogen are often necessary for adequate ERT. Unfortunately, such doses would have limited utility because of associated problems with toxicity and increased incidence of some forms of cancer. Therefore, the usefulness of such a method of treatment is quite limited.
A need exists for compositions and methods for administering estrogen-related quinols to individuals who require hormone replacement therapy. Furthermore, there exists a need for a therapeutically effective estrogen compound that retains its therapeutic activity while minimizing estrogenic proliferative effects in the uterus and breast.